The major goals of this work are the elucidation of the roles of COX-1 and COX-2 in the tumorigenesis process. We have demonstrated that COX-1 and COX-2 deficiencies as well as COX-1 and COX-2 specific inhibitors reduce skin tumorigenesis. To continue these studies, we used a keratinocyte grafting model. We transfected primary wild type, COX-1-/- and COX-2-/- keraticytes with a retrovirus containing v-ras and grafted the transfected keratinocytes on to the back of athymic nude mice and followed tumor development. Tumor growth from transfected COX-2 -/- keratinocytes was markedly reduced compared to transfected WT and COX-1-/- keratinocytes. Tumor incidence was also reduced in mice grafted with the COX-2 -/- keratinocytes. We found that lower proliferation rates and higher levels of terminal differentiation of the COX-2 -/- keratinocytes were main reasons which caused their development into fewer and smaller tumors in this grafting model.